Singh Bhumika, Martínez-Noa Yisel, Perez Alberto
Department of Chemistry, University of Florida, Gainesville, FL, USA.
These authors contributed equally to this work.
bioRxiv. 2025 Aug 2:2025.07.31.667969. doi: 10.1101/2025.07.31.667969.
Linear peptides play essential roles in biology and drug discovery, frequently mediating protein-protein interactions through short, flexible motifs. However, their structural plasticity-ranging from disordered to context-dependent folding-makes them challenging targets for molecular simulations. In this work, we benchmark the performance of twelve popular and emerging fixed-charge force fields across a curated set of twelve peptides spanning structured miniproteins, context-sensitive epitopes, and disordered sequences. Each peptide was simulated from both folded (200 ns) and extended (10 s) states to assess stability, folding behavior, and force field biases. Our analysis reveals consistent trends: some force fields exhibit strong structural bias, others allow reversible fluctuations, and no single model performs optimally across all systems. The study highlights limitations in current force fields' ability to balance disorder and secondary structure, particularly when modeling conformational selection. These results offer practical guidance for peptide modeling and establish a benchmark framework for future force field development and validation in peptide-relevant regimes.
线性肽在生物学和药物发现中发挥着重要作用，常通过短而灵活的基序介导蛋白质-蛋白质相互作用。然而，它们的结构可塑性——从无序到依赖上下文的折叠——使其成为分子模拟的具有挑战性的目标。在这项工作中，我们在一组精心挑选的12种肽上对12种流行和新兴的固定电荷力场的性能进行了基准测试，这些肽涵盖结构化微型蛋白质、上下文敏感表位和无序序列。每个肽都从折叠态（200纳秒）和伸展态（10秒）进行模拟，以评估稳定性、折叠行为和力场偏差。我们的分析揭示了一致的趋势：一些力场表现出强烈的结构偏差，另一些力场允许可逆波动，没有一个单一模型在所有系统中都能表现最佳。该研究突出了当前力场在平衡无序和二级结构方面的能力限制，特别是在模拟构象选择时。这些结果为肽建模提供了实用指导，并为未来在肽相关领域的力场开发和验证建立了一个基准框架。
